Immune Regulation in Human Filariasis

Abstract

Vector transmitted diseases such as the tropical helminth infections onchocerciasis and lymphatic filariasis (LF) affect more than 150 million people worldwide and are both considered major public health concerns. In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are engulfed by mosquito vectors and the current strategy to eliminate filarial infections focuses upon interrupting this transmission through annual mass drug administration (MDA). Nevertheless, repeated rounds of drug intake are needed to interrupt the lifecycle and gathering information about immunological processes could reveal alternative approaches in order to break transmission. Filariasis results in different pathological outcomes ranging from asymptomatic individuals to patients with severe pathology. Recently, a subgroup of asymptomatic latently infected patients has become apparent in LF; these individuals are amicrofilaremic despite chronic infection. With regards to immunological aspects, this subgroup has been neglected so far even though they are of special interest since they represent a roadblock in terms of parasite transmission. Moreover, immunological facets of asymptomatic microfilaremic (patent) individuals have been intensively described in the literature but usually in comparison to patients suffering from severe pathology. In onchocerciasis, most patients are patently infected and are characterized by weak or even absent inflammation. Interestingly, however, some infected individuals who lack severe pathology are amicrofilaremic and is considered to be a result of repeated MDA. Therefore, the present thesis aimed at analyzing the immune responses of a large cohort of LF or onchocerciasis infected individuals characterized by the absence or presence of MF. In addition, the signaling pathway of interleukin 10 (IL-10) was investigated since it is known from the literature that this immunosuppressive cytokine is a key player during filariasis. Results from infected individuals were compared with those from infection-free volunteers from the same endemic areas. In cases of infection with LF, immune profiles were also determined following the administration of different treatment regimes. Within this thesis it was shown that amicrofilaremic individuals could be characterized by lower parasite burden but increased immune responses with regards to their cytokine and antigen-specific immunoglobulin levels. In contrast, the presence of worm offspring was associated with a down-regulation of these immune responses but was not sufficient to induce the same immunomodulation in cells from non-endemic healthy blood donors in in vitro experiments. Moreover, analyzing gene expression profiles of regulatory, CD4⁺ and CD8⁺ T cell populations from individuals with patent and latent LF infection strengthened the observation that both groups of individuals cannot only be separated due to the presence or absence of MF per se but also due to differences in their immune profiles. These data provide novel insights into possible mechanisms which either actively hinder the release of MF from adult worms or their migration to the periphery in amicrofilaremic infected patients. Further research into these aspects may broaden the range of strategies currently employed to reduce transmission and in turn eliminate filariasis.